Turning the abundance of new drug compounds into clinically viable therapeutics is often limited by delivery issues stemming from low water solubility, poor stability, or high potency. Controlled-release from biodegradable polymer microspheres or microcapsules can provide sustained, localized drug delivery for a variety of such "problem" drugs. However, microparticle delivery can be limited by relatively imprecise control of drug delivery rates. The primary goal of this project is to investigate the effects of microparticle size and size distribution, and the shell thickness of microcapsules, on small molecule drug encapsulation and release. We have developed a novel method for fabrication of uniform polymer microspheres that allows precise control of the particle diameter. In addition, the technique provides a novel means to control the shell thickness of microcapsules. In preliminary studies, we have generated poly(lactideco- glycolide) (PLG) microspheres from -1 to 500 mu/m in diameter with narrow size distributions. We have also fabricated core-shell particles comprising aqueous, oil, and polymer (e.g. PLG) cores surrounded by polymer shells of variable thickness. By controlling the particle size, we showed we could achieve zero-order release of model drugs, and we have discovered several competing mechanisms by which particle size can affect release rates. In this study, we have chosen four model drugs that span a range of sizes and water solubilities: piroxicam, ciprofloxacin, ganciclovir, and cyclosporin. In the first aim, we will investigate the effects of microsphere size and drug/polymer properties on drug distribution in the microspheres, polymer degradation kinetics, and subsequent drug release rates. In the second aim, we will fabricate microcapsules with PLG-drug cores and polylactide (PLA) shells of varying thickness in order to examine the effect of shell thickness on prolonged release of these drugs. We will analyze each formulation for drug distribution and release during standard in vitro release experiments. To now, the effects of microparticle size on the factors controlling release rates have been obscured by typical broad particle size distributions. Thus, this project will provide novel fundamental insights into how to control drug release rates. In addition, we anticipate that this exploratory/developmental project (R21) will expand this technique to peptide-, protein-, and gene-based therapies, adding significantly to the medical impact of controlled release drug delivery.